Integrins are a superfamily of cell adhesion receptors, which are heterodimeric transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include the vitronectin receptor αvβ3. The vitronectin receptor αvβ3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions.
For example, the αvβ3 receptor expressed on the membrane of osteoclast cells has been postulated to mediate the bone resorption process and contribute to the development of osteoporosis [Ross, et al., J. Biol. Chem., 1987, 262: 7703]. As another example, the αvβ3 receptor expressed on human aortic smooth muscle cells has been postulated to stimulate their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty [Brown, et al., Cardiovascular Res., 1994, 28: 1815].
The connection between antagonism of the vitronectin receptor and restenosis after vascular procedures was referred to by Choi et al, J. Vasc. Surg., 1994, 19:125–34. International Patent Publication No. WO95/25543, published Mar. 9, 1995, refers to a method of inhibiting angiogenesis by administering an antagonist of the vitronectin receptor.
Additionally, a recent study referred to an αvβ3 antagonist as promoting tumor regression by inducing apoptosis of angiogenic blood vessels [P. C. Brooks, et al., Cell, 1994, 79: 1157–1164]. Similarly a murine monoclonal antibody LM609 developed to the vitronectin receptor reported in International Patent Publication No. WO89/05155, published Jun. 15, 1995, was referred to as useful in the inhibition of tumor growth. See, also, D. A. Cheresh et al, Cell, 1989, 57:59–69.
While passive immunotherapy employing monoclonal antibodies from a heterologous species (e.g., murine) has been suggested as a useful mechanism for treating or preventing various diseases or disorders, one alternative to reduce the risk of an undesirable immune response on the part of the patient directed against the foreign antibody is to employ “humanized” antibodies. These antibodies are substantially of human origin, with only the Complementarity Determining Regions (CDRs) and certain framework residues that influence CDR conformation being of non-human origin. Particularly useful examples of this approach for the treatment of some disorders are disclosed in PCT Application PCT/GB91/01554, Publication No. WO 92/04381 and PCT Application PCT/GB93/00725, Publication No. WO93/20210.
A second and more preferred approach is to employ fully human mAbs. Unfortunately, there have been few successes in producing human monoclonal antibodies through classic hybridoma technology. Indeed, acceptable human fusion partners have not been identified and murine myeloma fusion partners do not work well with human cells, yielding unstable and low producing hybridoma lines.
Novel human mAbs or humanized antibodies are particularly useful alone or in combination with existing molecules to form immunotherapeutic compositions. There remains a need in the art for fully human mAbs to vitronectin receptor αvβ3 or humanized antibodies thereto which can selectively block the integrin αvβ3 and display a long serum half-life.